The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy

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Kilpeläinen , T P , Hellinen , L , Vrijdag , J , Yan , X , Svarcbahs , R , Vellonen , K-S , Lambeir , A-M , Huttunen , H , Urtti , A , Wallen , E A A & Myohanen , T T 2020 , ' The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy ' , Biomedicine & Pharmacotherapy , vol. 128 , 110253 . https://doi.org/10.1016/j.biopha.2020.110253

Titel: The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy
Författare: Kilpeläinen, Tommi P.; Hellinen, Laura; Vrijdag, Johannes; Yan, Xu; Svarcbahs, Reinis; Vellonen, Kati-Sisko; Lambeir, Anne-Marie; Huttunen, Henri; Urtti, Arto; Wallen, Erik A. A.; Myohanen, Timo T.
Upphovmannens organisation: PREP in neurodegenerative disorders
Division of Pharmacology and Pharmacotherapy
Drug Research Program
Neuroscience Center
Regenerative pharmacology group
Henri Juhani Huttunen / Principal Investigator
Drug Delivery Unit
Division of Pharmaceutical Biosciences
Division of Pharmaceutical Chemistry and Technology
Pharmaceutical Design and Discovery group
Erik Wallen / Principal Investigator
Faculty of Pharmacy
Divisions of Faculty of Pharmacy
Datum: 2020-08
Språk: eng
Sidantal: 10
Tillhör serie: Biomedicine & Pharmacotherapy
ISSN: 0753-3322
DOI: https://doi.org/10.1016/j.biopha.2020.110253
Permanenta länken (URI): http://hdl.handle.net/10138/319279
Abstrakt: Previous studies have shown that prolyl oligopeptidase (PREP) negatively regulates autophagy and increases the aggregation of alpha-synuclein (alpha Syn), linking it to the pathophysiology of Parkinson's disease. Our earlier results have revealed that the potent small molecular PREP inhibitor KYP-2047 is able to increase autophagy and decrease dimerization of alpha Syn but other PREP inhibitors have not been systematically studied for these two protein-protein interaction mediated biological functions of PREP. In this study, we characterized these effects for 12 known PREP inhibitors with IC50-values ranging from 0.2 nM to 1010 nM. We used protein-fragment complementation assay (PCA) to assess alpha Syn dimerization and Western Blot of microtubule-associated protein light chain 3B II (LC3B-II) and a GFP-LC3-RFP expressing cell line to study autophagy. In addition, we tested selected compounds in a cell-free alpha Syn aggregation assay, native gel electrophoresis, and determined the compound concentration inside the cell by LC-MS. We found that inhibition of the proteolytic activity of PREP did not predict decreased alpha Syn dimerization or increased autophagy, and we also confirmed that this result did not simply reflect concentration differences of the compounds inside the cell. Thus, PREP ligands regulate the effect of PREP on autophagy and alpha Syn aggregation through a conformational stabilization of the enzyme that is not equivalent to inhibiting its proteolytic activity.
Subject: Serine protease
Alpha-Synuclein
Autophagy
Parkinson's disease
Protein conformation
ACTIVE-SITE
CELL
KYP-2047
PROTEIN
BRAIN
ENDOPEPTIDASE
PROLINE
317 Pharmacy
Referentgranskad: Ja
Licens: cc_by
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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